HIGH-FREQUENCY INDUCTION OF CHROMOSOMAL REARRANGEMENTS IN MOUSE GERM-CELLS BY THE CHEMOTHERAPEUTIC AGENT CHLORAMBUCIL

Recent mutagenesis studies have demonstrated that the chemotherapeutic agent, chlorambucil (CHL), is highly mutagenic in male germ cells of the mouse. Post-meiotic germ cells, and especially early spermatids, a re the most sensitive to the cytotoxic and mutagenic effects of this a gent. Genetic, cytogenetic and molecular analyses of many induced muta tions have shown that, in these germ-cell stages, CHL induces predomin antly chromosomal rearrangements (deletions and translocations), and m utation-rate studies show that, in terms of tolerated doses, CHL is pe rhaps five to ten times more efficient in inducing rearrangements than is radiation exposure. Appropriate breeding protocols, along with kno wledge of the advantages and limitations associated with the use of CH L, can be used to expand the current resource of chromosomal rearrange ments in the mouse and to provide new phenotype-associated mutations a menable to positional-cloning techniques. The analysis of CHL-induced mutations has also contributed to understanding the factors that affec t the yield and nature of chemically induced germline mutations in mam mals.